Author information
- 1
- a Department of Pharmacy and Pharmacology , Antoni van Leeuwenhoek Hospital/MC Slotervaart , Amsterdam , The Netherlands.
- 2
- b Department of Clinical Pharmacology , the Netherlands Cancer Institute , Amsterdam , the Netherlands.
- 3
- c Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology , Utrecht University , Utrecht , the Netherlands.
Abstract
OBJECTIVE:
A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug’s low solubility in water and to conduct proof-of-concept clinical studies.
SIGNIFICANCE:
Elacridar is highly demanded for proof-of-concept clinical trials that study the drug’s suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride.
METHODS:
Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 °C, +2-8 °C and -20 °C.
RESULTS:
The ASD powder was composed of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at -20 °C.
CONCLUSIONS:
The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.
KEYWORDS:
Elacridar; GF120918; GG918; P-gp; absorption; brain penetration; dissolution; freeze drying; solid dispersion; spray drying